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Marked clinical difference between two sibs affected with juvenile metachromatic leukodystrophy
J T Clarke1, M A Skomorowski, P L Chang
1Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Abstract:
In a child with enzymatically and histopathologically proven metachromatic leukodystrophy (MLD), the disease pursued a course typical of juvenile MLD characterized by neurological degeneration beginning at age 9 years and ending in death at age 18. A younger brother of the patient was found to have profound deficiency of arylsulfatase A in leukocytes and to excrete five- to 20-fold greater-than-normal amounts of sulfatide in the urine. He was completely free of symptoms attributable to MLD until age 16 when he developed acute cholecystitis caused by sulfatide accumulation in the gallbladder. Results of detailed neurological examination at age 21 years were normal; formal psychometric assessment showed a full-scale IQ of 105 (Wechsler). Studies on cultured skin fibroblasts from the brother showed defects in arylsulfatase A activity, measured with the use of synthetic and natural substrates, and in radiolabeled sulfatide turnover. Cellulose acetate gel electrophoresis of fibroblast extracts from the patient showed no detectable arylsulfatase A isozyme under conditions that clearly distinguished pseudo-arylsulfatase A deficiency from classical MLD. Biochemically, the patient was indistinguishable from patients with classical MLD; on the other hand, his clinical course is dramatically more benign than that of his sister who was affected with severe MLD.
Insights
A rare form of metachromatic leukodystrophy (MLD) presented with a milder clinical course in one sibling despite biochemical similarities to severe MLD. This suggests potential factors influencing MLD
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Metachromatic leukodystrophy (MLD) is a rare genetic disorder.
- It is characterized by the accumulation of sulfatides in the body.
- Deficiency in arylsulfatase A enzyme activity is a hallmark of MLD.
Observation:
- A patient with juvenile MLD experienced typical neurological degeneration.
- A sibling with similar biochemical MLD markers showed a significantly milder clinical course.
- The sibling developed acute cholecystitis at age 16 due to sulfatide accumulation.
Findings:
- The sibling exhibited profound arylsulfatase A deficiency and increased urinary sulfatides.
- Fibroblast studies confirmed defects in arylsulfatase A activity and sulfatide turnover.
- Electrophoresis indicated no detectable arylsulfatase A isozyme, distinguishing it from pseudo-deficiency.
Implications:
- The findings suggest that factors beyond arylsulfatase A deficiency influence MLD's clinical presentation.
- This case highlights the potential for milder MLD phenotypes.
- Further research into genetic or environmental modifiers of MLD is warranted.